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Neuropathic Central Pain
Epidemiology, Etiology, and Treatment Options
Robert J. Schwartzman, MD;
John Grothusen, PhD;
Thomas R. Kiefer, MD;
Peter Rohr, MD
Arch Neurol. 2001;58:1547-1550.
ABSTRACT
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Background Nociceptive pain is a major problem in clinical neurology. Peripheral
nerve injury may change the physiology of the dorsal horn so that pain becomes
progressively centralized.
Objective To review mechanisms underlying the plasticity of dorsal root ganglia
and dorsal horn neurons that lead to central pain from a peripheral nerve
injury.
Results Evidence is reviewed that points to molecular changes in nociceptive
terminals, ectopic firing of afferent pain fibers at the level of the dorsal
root ganglia, and physiologic changes of the N-methyl-D-aspartate receptor
that cause chronic nociceptive pain.
Conclusions Central sensitization is the physiologic manifestation of many severe
peripherally induced pain states. It is maintained by nociceptive input and
a physiologic change in the N-methyl-D-aspartate receptor. It consists of:
(1) hypersensitivity at the site of injury; (2) mechanoallodynia; (3) thermal
hyperalgesia; (4) hyperpathia; (5) extraterritoriality in the case of complex
regional pain syndrome/reflex sympathetic dystrophy; and (6) associated neurogenic
inflammation, autonomic dysregulation, and motor phenomena.
NOCICEPTIVE central pain is an emerging concept.1
It is well established that direct injury to the brain or spinal cord may
be followed by pain but it is not generally realized that damage to peripheral
nociceptive nerve endings in soft tissue, plexuses, or the nerves themselves
also causes nociceptive central pain.2 Inflammatory
conditions such as arthritis, infection, and chemical irritation of peripheral
tissues share many of the features noted following peripheral nerve damage.3 A fundamental difference between inflammatory pain
with tissue hypersensitivity and neuropathic pain is that in the former the
pain is relieved when inflammation has resolved and in the latter it may persist
after healing of the primary event.
The epidemiology of central pain following stroke, spinal cord injury,
or during the course of multiple sclerosis, brain injury, or trauma to the
central nervous system, is much better understood than that following peripheral
nociceptive injury.4 Approximately 1% to 8%
of patients with stroke have central pain, whereas 10% to 30% of patients
with spinal cord injury are affected during the course of their illness.5 There are no data on the number of patients who have
nociceptive peripheral pain from small fiber neuropathies, radiculopathy,
brachial, or lumbosacral plexopathies, complex regional pain syndrome, or
inflammatory peripheral conditions. However, because of the common nature
of the underlying causes, there may be many patients who have this problem.
The major clinical features of nociceptive central pain are (1) hypersensitivity
at the site of injury; (2) mechanoallodynia; (3) thermal hyperalgesia6; (4) hyperpathia7;
(5) extraterritoriality (regional distribution of pain) in the case of complex
regional pain syndrome/reflex sympathetic dystrophy8;
and (6) associated neurogenic inflammation, autonomic dysregulation, and motor
phenomena that are especially found in complex regional pain syndrome/reflex
sympathetic dystrophy.9
Central sensitization is the pivotal physiologic phenomenon underlying
the clinical symptoms of neuropathic central pain following peripheral nerve
injury.10 Central sensitization is primarily
induced by the firing of unmyelinated nociceptive C-fibers that project to
the superficial layers of the dorsal horn (DH).11
These fibers produce slow excitatory postsynaptic potentials that may last
for up to 20 seconds. Brief repetitive afferent nociceptive fiber input causes
temporal summation of these slow potentials, which induces the "wind-up" phenomenon
in central pain-projecting neurons (CPPNs). In this state, subsequent C-fiber
input produces a progressive increase in action potential output of CPPNs.
The gain of this neuronal response is controlled by an activity-dependent
N-methyl-D-aspartate (NMDA) receptor.12
The major mechanisms that underlie nociceptive central pain are (1)
autosensitization of nociceptive receptors; (2) ectopic firing of dorsal root
ganglia (DRG) cells; (3) calcium-induced molecular cascades from excess nociceptor
glutamate; (4) phenotypic change of afferent Aß-fibers and DRG cells
to the characteristics of those associated with pain; (5) changes in gene
expression of sodium channels and neuropeptides both at nociceptive terminals
and at the DRG; and (6) anatomic changes of the superficial layers of the
DH. This is a progressive but plastic process that is clearly reversible in
its early stages and requires nociceptive input for its maintenance.
A sharp distinction between an inflammatory and a primarily neuropathic
process at the site of injury cannot be made. Specifically, inflammatory lesions
may injure polymodal C-fiber nociceptors, while soft tissue injuries release
algesic molecules and induce cytokines that may damage these same nociceptors.
Either form of tissue injury increases the local production and retrograde
transport of nerve growth factors and other small molecules that may affect
the DRG and the DH.13 Transducer proteins and
the ion channels of nociceptor receptors generate depolarizing currents to
specific external stimuli at the site of injury. Irritant chemicals and a
low pH stimulate vanilloid, acid-sensing ionic channels, and purine transducer
proteins. Noxious heat stimulates vanilloid and vanilloid-like 1 receptors.14
Sensitization of nociceptive terminals occurs from repeated stimulation,
which causes a decreased threshold of activation, an increased response to
a given stimulus, and spontaneous depolarization. These changes are rapid
following injury and are secondary to conformational changes of the transducer
proteins or increased influx of calcium into the nociceptive terminals that
activate secondary messenger systems. This sensitization is induced by neurotrophic
factors, algesic molecules, leukotrienes, and cytokines released at the site
of injury.15 Sensitization of nociceptive terminals
is responsible for a component of primary hyperalgesia of injured tissue,
while the remainder is due to the hyperexcitability of CCPNs of the DH.16
The molecular mechanisms that underlie this sensitization of terminal
nociceptors are activation of intracellular kinase membrane-bound receptors17 and phosphorylation of tetrodotoxin-resistant sensory
neuron–specific sodium ion channels.18
Functional changes also occur in the peptide profile of primary afferent nociceptive
fibers following injury, which are important in this process.19
Present evidence supports the central importance of the NMDA receptor
of the DH in the induction and maintenance of central sensitization observed
in many chronic pain states.20 In the setting
of a maintained C-fiber nociceptive input, the magnesium blockade of the NMDA
receptor on CPPNs is lifted because of cumulative depolarization by summated
nociceptor-evoked slow synaptic potentials. Increased intracellular calcium
influx by enhanced NMDA gating is effected by several signaling cascades that
include (1) G protein–coupled neurokinin receptors and receptor tyrosine
kinases; (2) phosphokinases21; and (3) presynaptic
NMDA receptors.22 Important calcium-dependent
second messenger cascades initiated from persistent injury generate nociceptive
input that sustains CPPN plasticity. The maintenance of this plasticity is
further enhanced by activation of A primary afferent fibers that synapse
on inhibitory  -aminobutyric acid (GABA)/glycinergic interneurons of
DH lamina II and initiate long-term depression of inhibitory DH circuitry.23
Structural changes in pain systems occur after nociceptive terminal
tissue injury. These are effected by local increased production of growth
factors from fibroblasts, macrophages, and lymphocytes, which are retrogradely
transported back to the DRG and substantia gelatinosa. Their effects are reflected
by alterations of growth associated with structural proteins, G protein–coupled
receptors, transmitters, and synaptic modulators.1
It has also recently been demonstrated that electrical potentials alone of
a damaged nerve after a prolonged injury can alter transcription in sensory
neurons that changes their neurophysiologic characteristics.24
Injury to peripheral nerves or their terminal twigs in soft tissue is
frequently associated with sympathetically maintained pain.25
Following experimental peripheral nerve injury, there is a proliferation of
DRG satellite cells and a change in their gene expression that is manifested
by upregulation of the p75 receptor and neurotrophins. The neuroactive cytokine,
leukemia inhibitory factor, which is induced at the site of injury and retrogradely
transported to the DRG, may initiate sympathetic nerve sprouting.26 This sprouting occurs around large-diameter touch
neurons and may be associated with mechanoallodynia.27
Nerve injury and inflammatory conditions also upregulate constitutively expressed
genes and induce novel genes.28 Sustained nociceptive
input induces transcriptional changes in CPPNs that are partly mediated by
induction of the mitogen-associated protein kinase/cyclic adenosine monophosphate-dependent
protein binding cascade. This cascade causes changes in DH receptors, neuropeptides,
and transmitters, further altering the neurophysiology of the DH.29
Ectopic firing of DRG nociceptive neurons induced by experimental nerve
injury is an important mechanism behind the constant nociceptive afferent
barrage critical to maintaining central sensitization. Induction and coexpression
of abnormal combinations of several types of sodium channels in DRG nociceptive
cell membranes following nerve injury may allow subthreshold membrane potential
oscillations to initiate ectopic firing.30
Nerve blocks may fail in chronic pain states since the nociceptive barrage
is generated far from the affected site. Pain is primarily limited in extent
and severity by segmental and descending activation of GABA and glycinergic
inhibitory interneurons.31 A major pathway
of central pain modulation originates in the periaqueductal gray (PAG) of
the midbrain, which contains a high concentration of opioid receptors and
peptides. Animal studies have shown that electrical stimulation or local application
of neuroactive substances into the PAG produces analgesia.32
Much of the output from the PAG projects to the rostral ventromedial medulla,
which in turn projects largely to the DH of the spinal cord. Activation of
the rostral ventromedial medulla electrically or chemically produces effects
similar to PAG activation. The resulting inhibition of nociceptive afferent
spinothalamic tract neurons is believed to involve descending cholinergic
and monoaminergic systems as well as activation of intrinsic glycinergic and
GABAergic DH inhibitory circuitry.33
The PAG is a major nociception integration site that receives afferent
fibers from the prefrontal and insular cortex, hypothalamus, amygdala, nucleus
cuneiformis, reticular formation, and the locus ceruleus. The rostral ventromedial
medulla is a major relay between the PAG and the spinal cord and has 2 types
of neurons: on-cells and off-cells, which modulate nociceptive input from
the spinal cord. Both types project to lamina I, II, and V of the DH and are
activated by stimulation of the PAG. Off-cells are activated and on-cells
are inhibited by morphine.33 Off-cells are
part of the descending inhibitory system mediated from the rostral ventromedial
medulla through the dorsolateral funiculi, while on-cells constitute a descending
nociceptive facilitation pathway traveling through the ventrolateral funiculi
to the DH. Descending facilitation may function to counterbalance descending
inhibition to maintain some degree of pain responsiveness.
Anatomic changes occur in the periphery, dorsal root ganglia, and DH
of the spinal cord during prolonged pain states.1
Peripheral nerve injury seems to preferentially affect C-fiber nociceptive
neurons to a greater degree than A-fiber neurons. In experimental pain models,
C-fiber–denervated territory in lamina II of the DH was shown to be
invaded by touch afferent fibers from lamina III and IV.34
As noted earlier, products of Wallerian degeneration—cytokines and neurotrophic
factors—were found to induce sympathetic nerve sprouting in the DRG
with consequent basket formation around large-diameter touch neurons. These
touch neurons may have undergone a phenotypic switch to pain neurons so that
a sympathetic discharge evoked pain. Most importantly, severe chronic pain
in the experimental pain model leads to the death of inhibitory interneurons
(small dark neurons) in lamina II of the DH, which may further facilitate
pain projections.35
Treatment of nociceptive central pain is difficult and frequently unrewarding.
The basic principles are (1) the identification and elimination of the underlying
pathologic mechanism that maintains central sensitization. These mechanisms
vary widely and include poorly healed fractures, neuromas, brachial plexus
traction injuries, unsuspected neuropathies, and radiculopathies; (2) the
use of nonsteroidal antiinflammatory drugs to reduce peripheral sensitization
and modulate the activity of nociceptors; (3) the use of tricyclic antidepressants
to induce sleep and decrease lancinating and burning neuropathic pain; (4)
a trial of Gebapentin, lamotrigine, and topamax; (5) intravenous lidocaine
for treatment of widespread hyperalgesia, allodynia, and hyperpathia; (6)
sympathetic blockade for complex regional pain syndrome/reflex sympathetic
dystrophy while patients are still sympathetically maintained; (7) dorsal
column stimulation for areas that can be completely covered by induced paraesthesia;
and (8) intrathecal therapies including morphine, clonidine, and GABA(b) agonists
when other less invasive therapies have failed.36
A recent report demonstrates that glial cell line-derived neurotrophic
factor prevented and reversed sensory abnormalities in the rat partial sciatic
nerve ligation pain model without affecting pain-related behavior in normal
animals. It is postulated that glial cell line-derived neurotrophic factor
reverses injury-induced plasticity of several sodium channel subunits. The
most exciting aspect of this report is the demonstration that glial cell line-derived
neurotrophic factor may reverse some aspects of central sensitization.37 Another drug under clinical investigation is ziconotide,
a selective neuronal N-type calcium channel blocker. Intrathecal ziconotide
has been shown to be more potent, longer lasting, and more antinociceptive
than morphine. It may also block aspects of central sensitization.38 These new developments offer hope to a large number
of patients.
AUTHOR INFORMATION
Accepted for publication July 18, 2001.
From the Department of Neurology, Medical College of Pennsylvania,
Hahnemann University, Philadelphia, (Drs Schwartzman and Grothusen); Department
of Anesthesiology and Intensive Care Medicine, University of Tuebingen, Tuebingen,
Germany (Dr Kiefer); and Department of Anesthesiology and Intensive Care and
Pain Medicine, University of Saarbruecken, Teaching Hospital of the University
of Saarland, Saarbruecken Germany (Dr Rohr).
Corresponding author and reprints: Robert J. Schwartzman, MD, Department
of Neurology, Hahnemann University Hospital, Broad and Vine Streets, MS 423,
Philadelphia, PA 19102-1192 (e-mail: robert.schwartzman{at}drexel.edu).
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SECTION EDITOR: DAVID E. PLEASURE, MD
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